Genomics,Multiomics

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Loss-of-function of PTPN2 promotes pathogenic loss of FoxP3+ in RORgt+ Tregs [ATAC-seq]


ABSTRACT: Genetic variants at the PTPN2 locus, which encodes the tyrosine phosphatase PTPN2, cause reduced gene expression and are linked to rheumatoid arthritis (RA) and other autoimmune diseases. PTPN2 inhibits signaling through the T cell and cytokine receptors and loss of PTPN2 promotes T cell expansion and CD4 and CD8-driven autoimmunity. However, it remains unknown whether loss of PTPN2 in FoxP3+ regulatory T cells (Treg) plays a role in autoimmunity. Here we show that a reduction in Ptpn2 expression, comparable to that reported in human carriers of autoimmune-predisposing PTPN2 variants, unexpectedly enhances the severity of autoimmune arthritis through a Treg-intrinsic mechanism. Mechanistically, we found that through dephosphorylation of STAT3, Ptpn2 inhibits IL-6-driven pathogenic loss of FoxP3 after Tregs have acquired RORgt expression, at a stage when chromatin accessibility for STAT3-targeted IL-17 associated transcription factors is maximized. We conclude that PTPN2 promotes FoxP3 stability in RORgt+ Treg and that loss of function of PTPN2 in Treg contributes to the association between PTPN2 and autoimmunity. Overall design: Chromatin Accessibility with ATAC-Sequencing for Th17 and Tregs in vivo and Tregs and exTregs isolated after in vitro culutre.

INSTRUMENT(S): Illumina HiSeq 2500 (Mus musculus)

ORGANISM(S): Mus Musculus

SUBMITTER: Mattias Svensson  

PROVIDER: GSE123486 | GEO | 2019-03-18

REPOSITORIES: GEO

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Genetic variants at the PTPN2 locus, which encodes the tyrosine phosphatase PTPN2, cause reduced gene expression and are linked to rheumatoid arthritis (RA) and other autoimmune diseases. PTPN2 inhibits signaling through the T cell and cytokine receptors, and loss of PTPN2 promotes T cell expansion and CD4- and CD8-driven autoimmunity. However, it remains unknown whether loss of PTPN2 in FoxP3+ regulatory T cells (Tregs) plays a role in autoimmunity. Here we aimed to model human autoimmune-predi  ...[more]

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